Each ExAC subject has ~54 variants classified as causing a genetic disorder, almost all of which are false positives. i.e. ExAC highlights how bad existing databases are — because of their reliance of studies of very small sample size

99% have a frequency of <1%; 54% are singletons (variants seen only once in the data set); 72% are absent from both 1000G and ESP data sets

It covers: one variant for every 8 base pairs (bp) within the exome intervals; 7.5% of all possible synonymous variants; 63.1% of possible CpG transitions (C to T variants, in which the adjacent base is G); 3% of possible transversions; 9.2% of other possible transitions

72% of LoF-intolerant genes have not yet been assigned a human disease phenotype despite clear evidence for extreme selective constraint

Filtering on the highest allele frequency in any one population (‘popmax’) rather than the average (‘global’) allele frequency was best for identifying pathogenic variants

“The abundance of rare functional variation in many disease genes in ExAC is a reminder that such variants should not be assumed to be causal or highly penetrant without careful segregation or case-control analysis”

“discovery of homozygous PTVs is markedly enhanced in the South Asian samples, which come primarily from a Pakistani cohort with 38.3% of individuals self-reporting as having closely related parents, emphasizing the extreme value of consanguineous cohorts for human knockout discovery”

Related stories

Many variants previously reported pathogenic are now considered benign, particularly as the result of large scale analyses that show some of these variants are fairly frequent in the population. This misclassification has particularly affected those of African descent, a study on cardiac variants reports. This is largely because of the lack of individuals of African descent in large scale population databases. http://www.nejm.org/doi/full/10.1056/NEJMsa1507092

In a paper entitled “Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities”, a group of academics make the case for policy to ensure non-hispanic whites do not get the majority of the benefits from genomics: http://content.healthaffairs.org/content/35/8/1367

Quest/Athena have replied to Amy William’s in the latest step in this genetic-testing drama. Recap: Athena, now owned by Quest, reported a mutation in the plaintiff’s son, Christian, as a Variant of Uncertain Significance. The variant is now reported as pathogenic for Dravet syndrome, a diagnosis which, if made at the time, would have altered Christian’s course of treatment and possibly saved his life (he died age 2). The report, issued in 2007, was sent to Christian’s clinical geneticist, with the recommendation that the parents be tested to assess whether or not the variant was de novo. Ms Williams says she never saw the report. Quest/Athena have asked for the case to be dismissed, and that decision is pending. “If allowed to go forward, legal experts believe that Williams v Quest/Athena could define what constitutes the standard of care for a genetic testing lab.” https://www.genomeweb.com/molecular-diagnostics/quest-athena-reply-plaintiffs-wrongful-death-lawsuit

A documentary about the Undiagnosed (http://www.undiagnosedfilm.com/) has spawned a consortium dedicated to extending genomic analysis of six undiagnosed individuals to contextual info beyond the genome. The participants (in academe and industry) met on the 16th August to assess their results, though the rest of us may have to wait until the film airs in early 2017 to hear how they did. This endeavor is a follow on from the CLARITY challenge.